The focus of this work has been to understand the molecular details that control the interaction of MHC molecules with NK receptors, T cell receptors, and with coreceptors such as CD8. These studies are dependent upon structural, functional, and biophysical analysis of the interaction of the molecules in question, and attempts are made to correlate binding properties with function and structure. Progress in the past year has been particularly fruitful with respect to: 1) the binding analysis of a large panel of MHC-I, beta2-microglobulin, and NK receptor (Ly49A) site directed mutants, that identify the major site of interaction to a large region that includes residues both of the MHC and of the beta2-m light chain; and 2) binding studies of Ly49C with H-2Kb. These studies have resolved a major controversy concerning the site of interaction of the murine lectin-like NK receptors with MHC-I and raise additional questions as to how receptors with limited, but degenerate specificity function.